Pulmonary transplantation is shown to be successful in the treatment of patients with end-stage pulmonary disease. However, pulmonary oedema or edema (both terms can be used interchangeably) following reperfusion of the transplant is a major clinical problem for which no efficient drug exists at this moment. In addition, recent evidence indicates that the endothelium plays an essential role in regulating the dynamic interaction between pulmonary vasodilatation and vasoconstriction and is a major target during ischemia/reperfusion and acute respiratory distress syndrome (ARDS)-related lung injury. Thus, given that pulmonary edema often results in lung transplant rejection and that there is a persistent shortage of lungs available for transplantation, there is an urgent need to efficiently prevent or treat pulmonary edema.
During ischemia and reperfusion (I/R), a typical induction of inflammatory cytokines like tumor necrosis factor-alpha (TNF) occurs. TNF is a pleiotropic cytokine, mainly produced by activated macrophages, that is synthesized as a transmembrane molecule that can be released by metalloproteinases from the cell surface into the circulation (Gearing et al., 1994). TNF has been shown to bind to at least two types of membrane-bound receptors, TNF receptor 1 (55 kD) and TNF receptor 2 (75 kD), that are expressed on most somatic cells, with the exception of erythrocytes and unstimulated T lymphocytes. TNF can be considered as a two-edged sword: indeed, when overproduced, TNF has been shown to be implicated in the pathology of various infectious diseases, such as LPS-induced sepsis (Beutler et al., 1985), cerebral malaria (Grau et al., 1987), as well as treatment-associated mortality in African trypanosomiasis (Lucas et al., 1993). In contrast, TNF was shown to be one of the most efficient protective agents against cecal ligation and puncture-induced septic peritonitis in mice and rats (Echtenacher et al., 1990, Alexander et al., 1991; Lucas et al., 1997) and to be implicated in host defense during pneumococcal pneumonia in mice (van der Poll et al., 1997). Moreover, mice deficient in TNF receptor 1 were shown to be significantly more sensitive to Listeria monocytogenes (Rothe et al., 1993; Pfeffer et al., 1993) and Mycobacterium tuberculosis infection (Flynn et al., 1995) as well as against fungal (Steinshamn et al., 1996) and Toxoplasma infections (Deckert-Schluter et al., 1998). Therefore, it becomes clear that apart from its detrimental effects during overproduction or during prolonged chronic secretion, TNF is also one of the most potent protective agents against infections by various pathogens. In this regard, peptides derived from TNF have been suggested to be used as treatment against disease (DE 3841759 to Böhm et al.)
Apart from exerting a plethora of effects mediated by the activation of its two types of receptors (TNF receptor 1, 55 kD, and TNF receptor 2, 75 kD), TNF can also mediate receptor-independent activities. The tip domain of TNF is located on the top of its bell-shaped structure and is spatially distinct from its receptor binding sites, that are localized at the base of the trimeric molecule (Lucas et al., 1994). This domain has lectin-like affinity for specific oligosaccharides, such as trimannose and diacetylchitobiose. Both TNF and the tip peptide of TNF are capable of mediating a trypanolytic activity by interfering with the lysosomal integrity of the trypanosome, a pH-dependent effect probably involving the insertion of TNF into the lysosomal membrane (Magez et al., 1997). Moreover, mutants of the tip peptide in which three critical amino acids (T(105); E(107); E(110)) were replaced by A, were completely unable to mediate this activity (Lucas et al., 1994). A mouse TNF (mTNF) triple mutant, T104A-E106A-E109A (referred to hereafter as triple mTNF), lacks the trypanolytic and lectin-like affinity to oligosaccharides as compared to wild type TNF. The triple mTNF has significantly reduced systemic toxicity as compared to wild-type mTNF in vivo, but retains its peritonitis-protective effect in a murine model (Lucas et al., 1997).
Another receptor-independent activity of TNF is its membrane-inserting and sodium channel forming capacity (Baldwin et al. 1996). Indeed, others have shown that TNF forms a Na+-channel in an artificial lipid bilayer model, an activity that is pH-dependent, probably because it requires the “cracking” of the trimer, thus exposing hydrophobic residues to the membrane (Kagan et al., 1992).
Recent observations have indicated that instillation of anti-TNF-neutralizing antibody into the lungs of rats 5 min before bacterial infection inhibits the increase in alveolar liquid clearance, which is known to be driven by a change in intracellular sodium content in the alveolar epithelial cells. Moreover, instillation of TNF in normal rats increases alveolar liquid clearance by 43% over 1 hour (Rezaiguia et al., 1997). Although the latter findings indicate that TNF might be used to induce alveolar liquid clearance, wild type TNF cannot be used therapeutically due to its high systemic toxicity. The present invention relates to the usage of a selected group of TNF-derived peptides which can, to our surprise, efficiently be used to induce edema resorption and which have, compared to wild type TNF, lost systemic toxicity.